Pathophysiology and cardiorespiratory consequences of interstitial lung disease - review and clinical implications: a special communication.

Pathophysiology and Cardiorespiratory Consequences of Interstitial Lung Disease--Review and Clinical Implications: A Special Communication Interstitial lung disease (ILD) is a serious lung affliction that, like chronic obstructive airway disease (COAD), can lead to severe functional impairment, morbidity, and mortality. Limitations of the existing literature have hindred the characterization of the cardiorespiratory responses of patients with ILD at rest and during exercise. One difficulty has been the lack of accurate patient descriptors related to ILD and the lack of understanding regarding the underlying pathology. Although ILD includes many disorders, they are often not clearly differentiated in the literature. In addition to the problems of categorizing patients with ILD, the literature often fails to differentiate among patients on the basis of disease severity, which further hampers the interpretation of clinical studies. Methodologic weaknesses in previous studies have further contributed to problems with interpretation of the literature.

Given that symptoms of cardiorespiratory disease become more problematic for patients during physical stress than at rest, exercise testing can be considered an essential component of the clinical evaluation. The acute and especially the long-term exercise responses of patients with ILD, however, have not been well studied. The paucity of such information has hampered advances in the long-term management and rehabilitation of patients with ILD. In contrast, exercise testing has had a major role in the management of patients with COAD for many years and will undoubtedly become more prevalent in the evluation of patients with ILD. Furthermore, the adaptive responses of patients with COAD to training are better understood compared with those of patients with ILD. The purposes of this review, therefore, are to synthesize the current literature with respect to the pathophysiology of the category of diseases termed ILD and to assimilate the most recent literature related to the cardiorespiratory responses at rest and during exercise of patients with ILD. A better understanding of those factors that limit the exercise capacity of patients with ILD will provide the basis for improved exercise prescription. To overcome some of the shortcomings in the literature, particular attention is given in this review to reporting current studies in which patient populations are defined and the severity of disease is addressed.

Etiology and Prevalence

Various etiological factors are responsible for ILD. Interstitial lung disease comprises over 130 diseases such as pneumoconiosis, extrinsic allergic alveolitis, sarcoidosis, and chronic fibrosis. [1,2] The disease can be localized (eg, lung abscess or suppurative pneumonitis) or diffuse (eg, inhalation of organic dusts or toxic fumes). [3] Various liver disorders, cigarette smoking, and a genetic predisposition can also lead to fibrotic lung disease. [4] No apparent cause, however, can be identified in the majority of patients with ILD. [2,4]

Sharma et al reported various causes of ILD and their relative incidence. [5] Fibrosis of the lung can result from bacterial, viral, and fungal infections. In addition, lung fibrosis may be associated with rheumatoid and collagen diseases such as rheumatoid arthritis and systemic lupus erythematosus. One percent to 9% of farming populations and 6% to 15% of pigeon breeders are afflicted with ILD. Interestingly, in the United States, sarcoidosis predominantly affects the Afro-American population with a ratio of 11 Afro-Americans to 1 Caucasian. Several years ago, a National Institutes of Health task force attempted to characterize the epidemiologic features of ILD. [2] Explanations for the epidemiological characteristics of ILD, however, have yet to be identified. Based on prevalence statistics for ILD, this task force projected hospital admissions for patients with nine of the most common ILDS (eg, pulmonary sarcoidosis, asbestosis) to be 142,500 in 1977 in the United States. (2) For the same period, the projected number of hospital admissions for asthma patients was 32,000. [2] These findings suggest that ILD is a significant clinical entity; however, many physical therapists have had minimal involvement with this disorder.

Pathophysiology and

Clinical Features of Interstitial

Lung Disease

About 40 years ago, Austrian et al coined the term "alveolar-capillary block" to describe arterial hypoxemia in patients with fibrotic lung disease. [6] Arterial hypoxemia was thought to result from thickened alveolar interstitium, which reduced the patient's diffusing capacity for carbon monoxide ([DL.sub.CO]). Later, however, Finley et al suggested that the alveolar-capillary membrane in interstitial pulmonary fibrosis (IPF) was affected in a non-uniform manner, leading to ventilation/perfusion ([V.sub.A]/Q) ratio mismatch and consequently to arterial hypoxemia. [7] More recently, [V.sub.A]/Q ratio mismatch has been reported to be the source of hypoxemia at rest in both mild and advanced fibrotic lung disease. [8,9]

Interstitial lung disease is characterized by inflammation of the lung parenchyma, which may resolve completely or progress to fibrosis. [10] Interstitial pulmonary fibrosis leads to the deposition of excessive connective tissue. Because some patients with ILD recover completely whereas others progress to chronic fibrosis, [9] Snider considered IPF a subset of ILD. [10] Interstitial pulmonary fibrosis can be subdivided into granulomatous and nongranulomatous types. The Figure shows some common diagnoses associated with IPF.

Although patients with ILD form a heterogeneous group with respect to disease etiology, they share some similar clinical, radiological, physiological, and pathological features. Finucane and Prichard reported that patients with ILD have abnormalities in alveolar function consistent with morphological changes of interstitial infiltration and fibrosis, intra-alveolar exudate, and alveolar replacement. [11] Functionally, these abnormalities can lead to reduced lung volume, increased expiratory flow at midlung volume, and decreased lung distensibility (ie, reduced lung volume change for a given pressure change). [8,11-13] The characteristic shift of the pressure-volume curve (down and to the right) [14] reflects increased lung elasticity in ILD, which resists lung expansion. [15-17] Patients with ILD, however, typically have negligible air-flow obstruction. [18,19] The [DL.sub.co] [20] is decreased, and arterial blood gas analysis may reveal hypoxemia in the absence of hypercapnia. [10,21]

Other abnormalities associated with ILD include increased resting heart rate, [8] pulmonary hypertension, [9,15] and impaired gas exchange. [16,22,23] These findings are common, especially in patients with advanced ILD. The hypoxic pulmonary vasoconstriction is believed to cause the increase in pulmonary vascular resistance, [9,15] hence increased work of the right ventricle. These patients commonly complain of shortness of breath on exertion [23] and, in severe cases, at rest. This limitation can lead to termination of a patient's employment and can severely compromise the quality of the patient's life.

Various studies have proposed serial exercise testing or pulmonary function tests to monitor disease progress and the effect of treatment in ILD. [1,17,21,24-29] Watters et al developed a composite clinical-radiographic-physiologic (CRP) scoring system to improve the accuracy of these measures, to classify the severity of idiopathic pulmonary fibrosis, and to quantify longitudinal changes. [29] The CRP scoring system is based on variables such as dyspnea, chest radiograph, spirometry, lung volume, [DL.sub.CO], alveolar-arterial oxygen partial pressure at rest, and exercise oxygen saturation ([Sac.sub.2]).

Physiologic predictors of exercise limitation in patients with ILD are summarized in Table 1. A decrease in [DL.sub.co] [11,17,18,26,30-32] and reduced pulmonary function measures [11,18,26,31,33,34] have received the most support as predictors of abnormal exercise response (eg, arterial oxygen desaturation). Cotes et al, however, reported that when minute ventilation (VE) at an oxygen uptake ([VO.sub.2]) fo 1 L/min during exercise was considered along with resting pulmonary function measures, the prediction of exercise limitation in patients with ILD improved significantly. [31]

The causes of morbidity and mortality of patients with ILD vary according to the specific underlying pathophysiology. In general, functional impairment has been reported to be least in patients with sarcoidosis and extrinsic allergic alveolitis and most severe in patients with idiopathic pulmonary fibrosis. [8,15,34,35]

Medical Management

Standard medical management of patients with ILD attempts to reduce the inflammatory response, decrease pulmonary hypertension, and increase arterial oxygenation. Drug therapy may include anti-inflammatory drugs such as corticosteroids, and immunosuppressive drugs may be used in advanced cases to inhibit the inflammatory process by suppressing a potential autoimmune response. [1,10,24,36] Oxygen therapy [8,35] and vasodilators [37-42] may also be prescribed. Risk et al reported that in patients with severe ILD and with a [DL.sub.co] of less than 30% of the predicted value, thromboxane [B.sub.2] ([TXB.sub.2]), a vasoconstricting agent, was selectively released during aerobic exercise. [43] The [TXB.sub.2] increased by more than 75% at the start of the exercise, whereas arterial oxygen pressure ([PaO.sub.2]) declined significantly in these subjects. Patients with less severe ILD and control subjects did not show these changes. Vasodilators such as nifedipine, hydralazine, and amrinone have been administered to patients with ILD, as well as to others with pulmonary hypertension and cor pulmonale, with varying degrees of success. [37-42 Rich et al concluded that nifedipine was the most effective pulmonary vasodilator in the treatment of patients with pulmonary hypertension secondary to ILD. [39] These investigators reported nifedipine increased cardiac output by augmenting stroke volume. At the same time, both systemic and pulmonary resistances and pressures were lowered. Sturani et al reported that patients with ILD showed improvement in hemodynamic indexes using nifedipine when compared with using supplemental oxygen. [42] Relatively little is known, however, regarding the role of therapeutic exercise in the management of patients with ILD. [44]

Physiologic Responses of

Patients with Interstitial Lung

Disease to Rest and Exercise

Rest Response

The effect of sleep on arterial desaturation in patients with ILD is controversial. Oxygen desaturation during sleep has been reported in some patients with ILD. [19, 35, 45, 46] One group of investigators reported severe oxygen desaturation during sleep with values even lower than those obtained during exercise. [45] Another study reported a decrease in [Sao.sub.2] from baseline levels during periods of snoring and REM (rapid eye movement) sleep in patients with ILD. [19] Other researchers, however, reported little change in [Sao.sub.2] between wakefulness and sleep in patients with ILD. [35, 46] The discrepancies among these studies could be explained by the presence of sleep disturbances in patients with ILD. When patients with sleep apnea and airway obstruction were excluded in these studies, however, the degree of oxygen desaturation during sleep in the remaining subjects with ILD was significantly reduced. Thus, nocturnal oxygen therapy does not appear to be necessary in those patients who have acceptable [Pao.sub.2] levels when awake. [35] Table 2 summarizes the cardiorespiratory function of patients with ILD during an awake restful state.

Resting VE has been reported to be normal for patients with sarcoidosis and fibrosing alveolitis secondary to ILD. [8] Jernudd-Wilhelmsson et al observed that patients with advanced ILD(X total lung capacity [TLC] = [is less than]65%, X [DL.sub.CO] = 36% of predicted value) had an increased VE and respiratory frequency and that resting [VO.sub.2] was 12% higher than expeced. [9] They also reported increased dead space volume ([V.sub.D]) ([V.sub.A]/Q ratio = [is greater than]100) and shunt ([V.sub.A]/Q ratio = [is less than].005). The [V.sub.A]/Q ratio averaged 1.5 with considerable dispersion compared with a normal [V.sub.A]/Q ratio of 0.8. Similar findings have been reported in patients with various types of lung disease. [47, 48] Huang et al reported hypoxemia at rest in about 43% of the patients with ILD. [21] All patients, however, had a normal increase in [PaO.sub.2] when given 100% oxygen, indicating the presence of lung units with a low [V.sub.A/Q] ratio at rest.

Cardiopulmonary hemodynamics have been reported to be abnormal at rest in patients with ILD. Pulmonary vascular resistance (PVR) and pulmonary arterial pressure (PAP) are increased, whereas pulmonary capillary wedge pressure can be within the normal range. [15,42,49] In patients with severe ILD, the PVR can be 50% greater than normal at rest and can remain unchanged during exercise, whereas the systemic mean arterial pressure and cardiac output are within normal limits. [9] Another study, however, reported a low cardica index at rest in a variety of patients with cor pulmonale, including patients with ILD. [40] Resting tachycardia is common in patients with ILD. [8,50] This fact may reflect an increase in PAP or arterial desaturation at rest. Some investigators have proposed that pulmonary hypertension is due to fixed anatomical changes and to variable alveolar and arterial hypoxia. [15,51] In addition, Hawrylkiewicz et al proposed that pulmonary hypertension in patients with ILD is influenced by the large negative intrapleural pressure needed to inflate fibrotic lungs. [49] It has been shown with an animal model, however, that IPF attenuates hypoxic pulmonary vasoconstriction by changing perivascular pressure or by affecting the mechanisms inducing hypoxic pulmonary vasoconstriction. [52]

In summary, patients with ILD have various degrees of cardiovascular and pulmonary abnormalities at rest. Resting heart rate tends to be elevated. Minute ventilation, PVR, and PAP are also increased at rest. Nocturnal oxygen therapy for patients with ILD is indicated only when [PaO.sub.2] levels are abnormal and the patient is awake.

Submaximal Exercise Response

Table 3 summarizes the cardiorespiratory responses of patients with ILD to submaximal exercise. Several investigators have reported that VE is markedly increased in relation to [VO.sub.2] in patients with ILD, even at very low work rates. (*1) This increase in VE was affected by an increase in breathing frequency and by a decrease in tidal volume ([V.sub.T]) compared with healthy subjects. [8,32,53-56] Jones and Rebuck suggested that a person with a low vital capacity (VC) uses a relatively small proportion of VC for maximum tidal ventilation compared with a person with a higher VC. [55] Anderson and Bye concluded that the low compliance in combination with decreased TLC resulted in this pattern of breathing. [32]

Rapid, shallow breathing and resulting breathlessness are the most common clinical features of ILD. [23,33,53-56] Meerhaeghe et al reported exaggerated VE and inspiratory flow rate even at low work rates. [53] Although the inspiratory time (Ti)/total time of the respiratory cycle (Ttot) ratio, or duty cycle, is comparable to that of healthy subjects, both Ti and Ttot tend to be consistently shorter throughout exercise in patients with ILD. The normal duty cycle during exercise in patients with ILD is explained by the decrease in Ti, which parallels that of Ttot. Meerhaeghe et al suggested this breathing pattern reflected the use of a lower peak and total inspiratory muscle force, which may effectively delay the onset of respiratory muscle fatigue. [53]

In healthy subjects, the Ti/Ttot ratio increases from 0.35 at rest to 0.45 during moderate exercise. [57,58] During maximal exercise, however, no further increase in the duty cycle occurs, and the increase in inspiratory flow rate is mostly responsible for the increase in VE. [57] In healthy subjects, high VE during exercise is achieved by increasing breathing frequency, thus decreasing Ti and increasing the Ti/Ttot ratio while maintaining the TV at approximately 50% of the forced vital capacity (FVC).

With healthy subjects, there is a preferential distribution of ventilation and perfusion to the dependent lung zones because of the effect of gravity, with optimal [V.sub.A/Q] ratio matching occurring in the midzone of the lung. [59] During exercise, ventilation and perfusion are more evenly distributed throughout the lung. [59-61] Baker and Burki reported that the [V.sub.D/V.sub.T] ratio was affected by the ventilatory pattern during exercise in healthy subjects. [62] When ventilation was increased by increasing the [V.sub.T], the [V.sub.D/V.sub.T] ratio decreased even when the physiological [V.sub.D] increased. In contrast, changes in ventilation attributable to an increase in breathing frequency did not alter the [V.sub.D/V.sub.T] ratio or physiologic [V.sub.D]. Patients with pulmonary hypertension show no change in the [V.sub.D/V.sub.T] ratio and a significant increase in the [V.sub.A/Q] ratio during exercise. [63] Renzi et al have attributed the large [V.sub.D/V.sub.T] ratio found in exercising patients with ILD to reduce [V.sub.T], increased breathing frequency, and increased lung elasticity. [13] Furthermore, an increased physiologic [V.sub.D] and [V.sub.A/Q] ratio mismatch necessitated an increased ventilation to remove carbon dioxide. Jones et al have, perhaps, best characterized the normal ventilatory responses to increased ventilatory load. [64] They reported that patients with ILD respond to elastic loading by decreasing [V.sub.T] and increasing respiratory rate. Thus it is not surprising that patients with ILD, in view of their decreased lung compliance, adopt a rapid, shallow breathing pattern.

Occlusion pressure (pressure measured during sudden occlusion of the airway at the onset of inspiration) is a good index of the neutral output of the respiratory center (ie, central drive) and is independent of the resistance and compliance of the lung. [65,66] The occlusion pressure, and hence the respiratory drive, was reported to be increased in patients with ILD. [13,53] The increase in respiratory drive may reflect increased afferent reflex activity from the lung or chest wall. [13,53] Dimarco et al showed that patients with ILD typically have reduced [V.sub.T.S], decreased rib-cage expansion, and elevated occlusion pressure. [56] Minute ventilation and inspiratory air flow were also elevated. Some investigators report that patients with ILD have decreased pressure-generating ability of the inspiratory muscles, as demonstrated by reductions in both maximal transdiaphragmatic and maximal inspiratory airway pressures. [22,56] These investigators have concluded that neutral mechanisms such as vagal stimulation and mechanoreceptor stimulation in the chest wall increase respiratory drive and thereby alter the breathing pattern. The relative significance of these determinants of the breathing pattern, however, is unclear. [67]

Patients with a low [DL.sub.CO] at rest tend to desaturate during exercise. [30,32] Risk et al reported oxygen desaturation and decreased right ventricular ejection fraction in patients with severe ILD. [68] The right ventricular dysfunction, directly related to the severity of exercise-induced hypoxemia, was observed only during exercise and was reversed when patients breathed 100% oxygen. Spiro et al studied patients with fibrosing alveolitis and sarcoidosis and reported that a submaximal work rates, heart rate was significantly increased, stroke volume was reduced, and cardiac output was normal. [8] In contrast, Burdon et al observed normal heart rate responses when patients with ILD performed submaximal levels of exercise. [23] Patients with advanced ILD (ie, X VC = [is less than]50% of predicted value, X [DL.sub.CO] = [is less than]40% of predicted value), [69] however, showed elevated heart rate responses.

Cardiac hemodynamics can be compromised during exercise in patients with ILD. [15,41,42,49] During steady-state submaximal exercise, a significant increase in mean PAP has been reported. [49] The rise in mean PAP was correlated with a fall in [PaO.sub.2]. [49] Elevated mean PAP, PVR, and oxygen desaturation in response to exercise have also been reported in patients with idiopathic pulmonary fibrosis. [15] Lupi-Herrera et al reported no change in stroke index but did report an increase in cardiac index in exercising patients with ILD. [41] Increased right ventricular work in patients with ILD has also been reported. [42] The disproportionate increase in submaximal exercise heart rate similar to the resting tachycardia observed in patients with ILD [8,50] may reflect reduced [SaO.sub.2] or increased PAP. These explanations, however, do not rule out the effect of cardiorespiratory deconditioning in patients with ILD.

In summary, rapid, shallow breathing is prevalent in patients with ILD during submaximal exercise. The degree of oxygen desaturation observed depends on the severity of the disease. The ventilatory drive is apparently increased with an increase in [V.sub.D/V.sub.T] ratio and no change in the Ti/Ttot ratio. Pulmonary vascular resistance may increase, resulting in increased right ventricular work.

Maximal Exercise Response

Maximum power output is reduced in patients with ILD. [23,32,33] Bye et al reported that limitation of ventilatory capacity was principally responsible for the reduced maximum power output. [33] Thus, the ventilatory impairment in exercise results both from an increase in VE relative to [VO.sub.2] and a reduction in overall capacity to increase ventilation. [22,23] Table 4 summarizes the cardiorespiratory responses of patients with ILD to maximal exercise.

The pattern of breathing in patients with ILD at maximal exercise remains rapid and shallow, with maximum ventilation exceeding that predicted for a given [VO.sub.2] value and approximating the predicted maximum voluntary ventilation (MVV). [18,28,33,70] In contrast, healthy subjects usually cease maximal exercise with a considerable reserve of ventilation (ie, [is less than]70%-80% of MVV). [71,72] The Ti, Ttot, and duty cycle of the patients with ILD change little from submaximal to maximal exercise levels. [23,53,56]

Increased ventilation during exercise reflects inefficient gas exchange and possibly increased ventilatory drive. [11,56] Anderson et al reported that the maximum [V.sub.T] of patients with ILD achieved during exercise was 50% to 60% of the VC, which is comparable to that of healthy subjects. [32] The actual maximum [V.sub.T], however, was less in patients with ILD because of a reduced VC. The [V.sub.D./V.sub.T] ratio either did not change or increased because of the limited increase in [V.sub.T] and an increase in lung area with a high [V.sub.A]/Q ratio. Minute ventilation, therefore, necessarily increased to maintain a normal arterial carbon dioxide pressure ([Paco.sub.2]). Anderson et al observed that hypoxemia during exercise was common in patients with ILD. [32] They further postulated that a change in ventilatory drive resulted from carotid body stimulation secondary to hypoxemia.

During maximal exercise, [Sao.sub.2] is reduced, especially in patients with advanced ILD. (*1) A significant drop in [Pao.sub.2] and widening of the gradient for the difference in partial pressure of oxygen between alveolar gas and arterial blood during exercise have also been observed in patients with ILD. [8,9,28] Spiro et al reported that their patients with fibrosing alveolitis experienced "the sensation of dyspnea before fatigue." [8] They attributed the drop in [Pao.sub.2] observed in these patients to continued perfusion of poorly ventilated areas during exercise. Perfusion of well-ventilated areas may explain the constancy of the [V.sub.D./V.sub.T] ratio and [Paco.sub.2].

Jernudd-Wilhelmsson et al reported that during exercise the [V.sub.D./V.sub.T] ratio was unaltered and the shunt fraction increased slightly, whereas the [Paco.sub.2] did not change significantly. [9] The [V.sub.A]/Q ratio increased as a consequence of a disproportionate increase in VE relative to cardiac output. They attributed 30% of the increased gradient during exercise to limited [DL.sub.co] and the remaining 70% to mechanisms such as shunting and perfusion of regions with a low [V.sub.A]/Q ratio. Wagner attributed the fall in [Pao.sub.2] during exercise in patients with ILD to a diffusion defect and to a fall in mixed venous oxygen pressure. [73] Finucane et al reported that exercise-induced hypoxemia reflected impaired [DL.sub.co] and an abnormally high [V.sub.D./V.sub.T] ratio. [11]

Interestingly, the reduction in maximum power output did not appear to be related to either the absolute [Sao.sub.2] during maximal exercise or the exercise-induced fall in [Sao.sub.2]. No relationship existed between the degree of exercise-induced oxygen desaturation and the reduction in VC and TLC. [23] Bye et al observed that patients with ILD who have a forced expiratory volume in one second ([FEV.sub.1]) of less than 70% of the predicted value and a fall in [Sao.sub.2] greater than 3% to 5% during exercise can anticipate a marked improvement in exercise endurance with supplemental oxygen. [33] They further reported that maximal work capacity of patients with ILD did not increase with supplemental oxygen even though ventilation and blood lactate decreased. Thus, the endurance of these patients can increase, although maximum power output may not change. Bye et al concluded that the reduced ventilatory capacity associated with ILD was primarily responsible for limiting maximal work capacity. [33]

Aldrich et al hypothesized that the airways of patients with ILD are less susceptible to dynamic compression and that most of the expiratory air flow is effort-dependent, as indicated by alterations in the flow-volume loop. [22] In contrast, in healthy subjects and in patients with air-flow limitation, the expiratory air flows are largely effort-independent. [14,16,74,75] The recovery breathing pattern in patients with ILD has been reported to be similar to that of healthy subjects, suggesting pulmonary edema and respiratory muscle fatigue are not significant contributors to exercise intolerance. [76]

Gallagher and Younes demonstrated that inspiratory muscle fatigue does not occur during maximal exercise in patients with ILD. [76] In their study, maximum ventilation reached 76% of the predicted MVV for the patients with ILD, whereas the patients with COAD reached 111% of the predicted value. They reported no evidence to suggest that respiratory muscle fatigue had occurred in the patients with COAD. Thus, they inferred that the patients with ILD who were less stressed with respect to ventilatory demand similarly had no respiratory muscle fatigue.

Following maximal exercise in patients with severe ILD, Jernudd-Wilhelmsson et al reported cardiac output was increased by only 50% and pulmonary vascular pressure doubled, whereas the systemic circulatory changes were normal. [9] Other researchers reported that cardiac output failed to increase appropriately with exercise, presumably because of obliteration of the pulmonary vascular bed. [11, 41] Patients with ILD cease exercising at high levels of ventilation with a heart rate well below the predicted maximum value. [32, 33, 76]

In summary, patients with ILD tend to adopt a rapid, shallow breathing pattern. Different mechanisms have been proposed to explain this pattern. Although the breathing pattern during the recovery phase of exercise tends to be normal, various physiological mechanisms have been proposed to explain ventilatory limitation during exercise. Compared with healthy subjects, the [V.sub.D]/[V.sub.T] ratio of patients with ILD remains largely unchanged or increased. Ventilation/perfusion ratio mismatch is the chief cause of hypoxemia, both at rest and in exercise in patients with ILD, whereas [Paco.sub.2] usually remains within normal limits. A pulmonary diffusion defect has been proposed as an additional cause of hypoxemia during exercise in patients with ILD. Increased PVR and heart rate during exercise may occur in some patients. Limited ventilatory capacity is considered a prime factor in limiting the maximal work capacity of patients with ILD. Supplemental oxygen can increase endurance in patients with severe ILD, which may reflect a change in breathing pattern, hence a decrease in the work of breathing.

Clinical Implications

Although patients with ILD have limited ventilatory capacity and increased energy cost of breathing [14, 16] and are candidates for developing respiratory muscle fatigue, [22] therapeutic exercise and rehabilitation programs for these patients have received relatively little attention. [44] In contrast, numerous studies have been conducted on the effects of general and specific exercise programs for patients with COAD, [77-86] neurological problems such as quadriplegia, [87] muscular dystrophy, [88] and psychiatric problems. [89, 90] Furthermore, in light of new evidence for respiratory limitation to maximal exercise in elite athletes, [91-95 respiratory muscle training has been proposed even for highly conditioned athletes as a means of enhancing exercising performance. [16, 72, 75, 96, 97]

Because of the dearth of controlled trials examining the long-term exercise responses of patients with ILD, the literature on exercise training in the management of patients with lung disease is limited to studies of patients with COAD. Typically, patients with COAD can improve their physical endurance with training. This improvement, however, is not usually associated with increases in [Vo.sub.2 max] or oxidative muscle enzymes, as observed in healthy people, because the intensity of the training stimulus is often insufficient to elicit an aerobic exercise response. Rather, improved endurance is believed to reflect an increased threshold to dyspnea, improved mechanical efficiency, improved ventilatory muscle endurance, and increased motivation. [98] The degree to which patients with ILD respond to exercise training and the factors that contribute to improved perfromance need to be elucidated. Like patients with COAD, patients with ILD may not be physiologically capable of increasing their [Vo.sub.2 max] or power output with exercise. It is likely, however, that even low-intensity exercise for patients with ILD can improve their physical endurance and general cardiorespiratory conditioning. Thus, given that patients with ILD constitute a population that is pathophysiologically distinct from patients with COAD and that exhibits distinct cardiorespiratory responses at rest and during exercise, a unique approach to exercise training for these patients is warranted.

Some of the concerns that must be addressed when considering exercise programs for the patient with ILD are the resting and disproportionate exercise tachycardia, the existing or potential arterial desaturation, the rapid, shallow breathing pattern; and the possible increase in PAP and right ventricular work. This clinical presentation can be further confounded by the effects of cardiorespiratory deconditioning. Considering this clinical presentation, several points must be addressed when prescribing long-term exercise training for patients with ILD. First, the objectives of the training program must be clearly defined. Attempting to increase maximal work capacity, for example, may be less functionally significant than achieving optimal endurance and cardiorespiratory conditioning. "Optimal" endurance and cardiorespiratory conditioning is defined as the highest level of activity achievable with training that can be sustained over a period of time and that requires the least work of breathing and arterial oxygen desaturation possible without compromising the patient's overall physical well-being and comfort. Endurance activities are those that require high repetitions and low resistance. Such activities involve large muscle groups and include walking, either on a level surface or on a surface with a low grade, and ergometry with moderate to high cadence and low resistance. With respect to the components of exercise prescription such as optimal frequency, duration, and time course of training, these activities are based on each individual's objective and subjective responses to training. Subjective scales such as Borg's perceived exertion and breathlessness scales have a sound physiologic basis [64, 99-107] and can be used to monitor a patient's subjective responses during testing and training.

One way of reducing the work of breathing and improving the exercise capacity of a patient with ILD is the use of supplemental oxygen. [33] Supplemental oxygen is known to improve the endurance of patients with ILD during rigorous exercise, but an optimal dosage should be determined for a given work load to avoid compromising [Sao.sub.2] and increasing the sensation of breathlessness. The indications for oxygen during exercise for patients with ILD have not been firmly established. Clearly, patients needing oxygen at rest not only will require oxygen during exercise, but the dosage must be increased to meet the demand of the exercise being performed. For patients who do not require oxygen at rest, however, criteria must be established regarding the indications for oxygen during exercise and the appropriate dosage to be administered. The use of oxygen can be determined on the basis of whether patients can reach some arbitrary functional level of exercise. Alternatively, oxygen could be administered to enable patients to achieve a higher level of exercise during training. Maintaining patients' cardiorespiratory status at a high level in a rehabilitation program may enable them to perform at a higher level in their activities of daily living. The advantages and disadvantages of these alternatives have yet to be addressed, either philosophically or scientifically, for patients with ILD.

Conclusions

This article has reviewed the pathophysiology of ILD and its cardiorespiratory consequences at rest and during exercise. An understanding of the cardiorespiratory consequences of ILD at rest and during rigorous exercise will help to characterize the natural history of the disease, to differentiate cardiac and respiratory limitations to exercise, and to assess the functional consequences of the disease. In addition, a better understanding of the pathophysiology and cardiorespiratory consequences of ILD will enhance methods of clinical exercise testing, which are essential in assessing functional work capacity, dyspnea, disability, and occupational capability and in prescribing exercise programs. Descriptions of long-term exercise responses for patients with ILD are lacking in the literature. These descriptions are needed to characterize training responses for different categories of patients with ILD of various severities, to determine what intensity of training is apt to be beneficial, and to define the criteria for exercise prescription and thereby optimize the effects of training.

(*1) 9, 23, 28, 32, 33, 41, 53.

(*2) 8, 9, 18, 23, 28, 32, 33, 42.

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F Chung Msc, was a graduate student, School of Rehabilitation Medine, University of British Columbia, when this article was written.

E Dean, PhD, is Assistant Professor, School of Rehabilitation Medicine, University of British Columbia, 2211 Wesbrook Mall, Vancouver, British Columbia, Canada V6T 1W5. Address all correspondence to Dr Dean.

This work was supported in part by the British Columbia Lung Association and the Canadian Lung Association.

This article was submitted September 7, 1988; was with the authors for revision for 12 weeks; and was accepted May 9, 1989.